Photoreceptor cell degeneration resulting from uveitis is a major cause of blindness in the United States. This damage was initially believed to be due to the infiltration of macrophages into the outer retina. However, our preliminary studies suggest that retinal microglia could be the cells that initiate uveitis, leading to subsequent retinal damage. Retinal microglia were found to release reactive oxygen and nitrogen species, and to migrate from inner to outer retina/photoreceptor cell layer during the early phase of EAU prior to the infiltration of macrophages. Based on these novel findings, we propose to test two hypotheses: 1) In autoimmmune uveo-retinitis, activation and migration of retinal microglia to the outer retina occur first; 2) The migrated microglia generate inflammatory cytokines, attracting hematogenous phagocytes, including macrophages and PMNs, which amplify the destructive inflammation. We will test these hypotheses with the following Specific Aims: 1. Document the natural history of EAU and microglial migration to the photoreceptor cell layer in Y->X chimeras with optic nerve axotomy. 2. Evaluate generation of cytotoxic agents (cytokines and oxidants) by the migrated microglia in the early phase of EAU. 3. Evaluate photoreceptor cell damage at the site of microglial infiltration during the early phase of EAU. To assure successful completion of the specific aims, we have assembled a multidisciplinary team of experts to undertake the studies. Dr. Guey-Shuaug Wu has expertise in the areas of membrane lipid peroxidation and inflammatory cytokines. The principal investigator is experienced in the field of experimental uveitis, ocular pathology and free radical biology. Understanding the role of retinal microglia in the pathogenesis of uveitis could lead to the development of specific therapy directed against these retinal cells.